The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies indicate that: (1) While it is possible to differentiate D1 dopamine agonists in vitro on the basis of their intrinsic efficacy, differences in the efficacy of the drugs have not been correlated with any other observed pharmacological effect of these drugs. (2) Studies of the behavioral effects of the D1 dopamine agonist, SKF 38393, have indicated few of its behavioral effects are mediated by actions at D1 dopamine receptors. This finding is important because SKF 38393 is often used as a prototype D1 agonist. (3) Dopamine D1, but not dopamine D2, receptors are involved in the lethal effects of acutely administered cocaine. We are preparing D1 antagonists that do not penetrate the blood brain barrier. These drugs may serve as antidotes to acute cocaine overdose and will also serve as tools for the investigation of the function of the peripheral D1 dopamine system. (4) Dopamine D2 agonists can stimulate this behavior in a manner similar to the manner in which cocaine or amphetamine stimulate behavior, in contrast, D1 agonists do not. These differences suggest an involvement of D2 dopamine receptors in the stimulant behavioral effects, and a lack of involvement of D1 dopamine receptors. (5) The pharmacology of dopamine D2 agonists is being characterized in a cell line that expresses a D2 receptor that is functionally similar to brain dopamine D2 receptors. Because these D2 receptors are expressed in the absence of other dopamine receptor subtypes, this cell line is a model system for studying the function and regulation of the D2 receptor. The findings from these studies suggest that the dopamine D2 receptor regulates cyclase inhibition predominantly via the Gi1 and/or Gi2 subunits of G-alpha. Using this system the intrinsic efficacies of dopamine D2 agonists have been characterized. These studies also indicated an intriguing link between the Gi3 subunit and the Gi1 or Gi2 subunits. (6) The pharmacology of the putative D3 receptor agonist, 7-OH-DPAT, is being characterized. These behavioral and in vitro studies have indicated that 7-OH-DPAT is a weak partial agonist at D2 receptors, and several of its effects may be mediated by that activity rather than D3 agonist activity.